The present invention relates to copolymers of poly(alkylene oxides) and amino acids or peptide sequences, and more particularly to copolymers of polyalkylene oxides such as polyethylene glycol (PEG), with amino acids or peptide sequences. The present invention also relates to conjugates of such polymers formed with pharmaceutically active compounds covalently bonded to the amino acid or peptide sequence of the copolymer. The present invention further relates to ionically conductive materials, hydrogel membranes and semi-interpenetrating polymer networks prepared from the copolymers of the present invention.
The conjugation of biologically active polypeptides with water-soluble polymers such as PEG is well-known. The coupling of biologically active and pharmaceutically active peptides and polypeptides to PEG and similar water-soluble polymers is disclosed by U.S. Pat. No. 4,179,377 to Davis et al. Polypeptides modified with PEG are disclosed as exhibiting dramatically reduced immunogenicity and antigenicity. The PEG conjugates also exhibit a wide range of solubilities and low toxicity, and have been shown to remain in the bloodstream considerably longer than the corresponding native Compounds yet are readily excreted. The PEG conjugates have also been shown not to interfere with enzymatic activity in the bloodstream or the conformation of the polypeptides conjugated thereto. Accordingly, a number of PEG-conjugates of therapeutic proteins have been developed exhibiting reduced immunogenicity and antigenicity and longer clearance times, while retaining a substantial portion of the protein's physiological activity.
Attention has also focused upon the conjugation of PEG with therapeutic drugs. Gnanov et als., Macromolecules, 17, 945-52 (1984) observed that the attachment of PEG to various drugs led to prolonged pharmacological activity.
As disclosed in the above-cited U.S. Pat. No. 4,179,337, the conjugation of PEG begins with functionalization of the terminal hydroxyl groups of the polymer prior to coupling with a ligand of biological relevance, although some ligands are capable of covalently bonding to the terminal hydroxyl groups without functionalization. The foregoing is also disclosed in Zalipsky et al., J. Macromol. Sci-Chem., A21, 839-845 (1984); and Zalipsky et al., Eur. Polym. J., 19, 1177-1183 (1983). One of the limitations of PEG is that it has only two reactive end groups available for functionalization. This is a particularly severe design limitation for PEG chains of high molecular weight which contain only a very small number of reactive groups for any given weight of polymer. To circumvent this problem, several reaction schemes have been disclosed in which PEG chains were copolymerized with a variety of difunctional co-monomers. For example, Graham et al., Makromol. Chem. Macromol. Symp., 19, 255-73 (1988) and Imai et als., Makromol. Chem. Rapid. Commun., 5, 47-51 (1984) disclose copolymers of poly(oxyethylene) dicarboxylic acids with aliphatic and aromatic amines. Block copolymers of PEG with polyesters are disclosed by Wang et als., J. Macromol Sci-Chem., A26(2&3), 505-18 (1989). Block copolymers of PEG with poly(L-proline) are disclosed by Jeon et als., J. Polym. Sci. Part A Polym. Chem., 27, 1721-30 (1989). Block copolymers of PEG With poly(gamma-benzyl L-glutamate) are disclosed by Cho et al., Makromol. Chem., 191, 981-91 (1990). In these references, the use of the PEG block copolymers as biomaterials is suggested. Polyethylene glycols, cross-linked by copolymerization with triols and diisocyanates for use in the preparation of hydrogels and hydrogel membranes are disclosed by Kimura et als., Macromolecules, 16, 1024-6 (1983), Ouchi et als., J. Macromol. Sci-Chem., A24(9), 1011-32 (1987), and Bos et al., Acta Pharm Technol., 33(3), 120-5 (1987). The hydrogel and hydrogel membranes have been investigated as potential materials for controlled drug delivery. However, none of the above-disclosed PEG copolymers have the desirable structural feature of having multiple functional groups at regular, predetermined intervals that can be utilized for drug attachment or cross-linking reactions.
The preparation of PEG ionomers with phosphate diester linkages is disclosed by Pretula et als., Macromol. Chem. Rapid Commun., 9, 731-7 (1988), the apparently only known example of a strictly alternating copolymer of PEG. However, the reaction schemes developed by Pretula require highly reactive intermediates that need to be handled with extreme care. Consequently, the resulting copolymers have apparently not yet found any practical applications.
PEG copolymers having multiple pendant functional groups at regular predetermined intervals that can be utilized for drug attachment or cross-linking reactions would be highly desirable.